Case Reports Orbital Inflammation as a Presenting Sign for CREST Syndrome Shirin W. Hamed-Azzam, M.D.*, David P. D’Cruz, M.D., F.R.C.P.†, and David H. Verity, M.D., F.R.C.ophth.* Abstract: A 61-year-old male was referred with a week’s history of a painful and swollen left eye. Examination revealed normal visual acuities, left proptosis and global restriction of ocular ductions, and subretinal fluid at the macula. CT imaging confirmed thickening of the posterior scleral coat, with an associated choroidal effusion. Serology revealed positive antinuclear antibodies with a centromere staining pattern; subsequent rheumatology review revealed extensive telangiectasia with digital ulceration in both hands, and a diagnosis of limited cutaneous systemic sclerosis was made. Orbital inflammatory disease is often the initial presentation of systemic diseases such as sarcoidosis, granulomatosis with polyangiitis, and IgG4 disease. Limited cutaneous systemic sclerosis is rarely encountered in the context of orbital inflammation, but is a further systemic association, reminding the clinician of the diagnostic importance of peripheral symptoms and serological markers in patients presenting with orbital inflammation and scleritis.
S
ystemic sclerosis is a multisystem disorder of unknown etiology characterized by immune activation, vasculopathy, and marked fibroblast activity. Limited cutaneous systemic sclerosis, previously known as CREST syndrome, is a variant of systemic sclerosis characterized by Calcinosis cutis, Raynaud’s phenomenon, Esophageal dysmotility, Sclerodactyly and Telangiectasia.1 Systemic sclerosis is an uncommon disease, and ocular manifestations have been reported in a very small number of cases. Ocular symptoms can be particularly troublesome and may present long before the systemic diagnosis has been established. The authors describe a patient with limited cutaneous systemic sclerosis who presented with scleritis and dacryoadenitis, which to our knowledge has not previously been reported.
CASE REPORT A 61-year-old male patient of Indian extraction with no significant medical history was referred with a painful swollen left eye over the previous week. On examination, his best-corrected visual acuity was 6/9 in each eye, with no evidence of optic neuropathy. The objective findings included a 2 mm relative left proptosis and a moderate restriction of left ocular ductions in all positions of gaze with symptomatic diplopia being most severe in downgaze. The conjunctiva was injected and chemosed, both lids were swollen, and he was tender on palpation over lacrimal gland; bilateral intraocular pressures were normal. Although fundus examination revealed a healthy appearing optic disc, there was evidence of subretinal fluid in the nasal macula area clinically and on Optical Coherence Tomography imaging *Orbital Service, Moorfields Eye Hospital, and †Rheumatology Department, Guy’s and St Thomas; Hospital, London, United Kingdom Accepted for publication August 5, 2017. The authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to David H. Verity, M.D., F.R.C.Ophth, Moorfields Eye Hospital NHS Foundation Trust, City Road, London EC1V 2PD, United Kingdom. E-mail: David.verity@moorfields. nhs.uk DOI: 10.1097/IOP.0000000000001007
Ophthal Plast Reconstr Surg, Vol. XX, No. XX, 2017
(Fig. 1). CT imaging confirmed thickening of the left posterior sclera with an associated choroidal effusion and asymmetric enlargement of the lacrimal gland. Although there was no evidence of extraocular muscle involvement, there was stranding of the subcutaneous soft tissues over the malar, temporalis, and glabellar regions (Fig. 2), and ultrasound examination revealed nasal and temporal elevation due to choroidal effusions. On the presumptive diagnosis of marked scleritis with atypical features, he was treated with Co-amoxiclav (Tini Pharma, Delhi, India) 625 mg tid and a nonsteroidal inflammatory preparation (Flurbiprofen, Taj Pharmaceuticals Limited, Mumbai, India, 50 mg tid) for 1 week. Laboratory investigations revealed strong positivity to antinuclear antibodies of 1:2,560 with a centromere pattern, positive antineutrophil cytoplasmic antibodies, but negative proteinase 3 and myeloperoxidase antibodies. Although the thyroid-stimulating hormone was mildly raised, thyroid antibodies, free thyroxine, angiotensinconverting enzyme, sedimentation rate, and C-reactive protein were all negative or within the respective normal ranges. In view of these findings, he was referred for a rheumatology assessment, and on further questioning, he reported a single typical episode of Raynaud’s disease 20 years previously with a white phase to the discoloration. Three months after his orbital presentation, he then developed digital ulceration of both the hands and the feet, with discoloration of the fingernails and extensive telangiectasia; although there were no other typical features of limited cutaneous systemic sclerosis such as reduced aqueous tear production, breathlessness, dysphagia, or skin changes, he was diagnosed with limited cutaneous systemic sclerosis. In addition, Nailfold video capillaroscopy was performed and revealed very abnormal with grossly dilated capillaries, capillary drop out, and ragged cuticles in keeping with systemic sclerosis. His orbital inflammatory disease promptly responded to the above treatments. No further treatment was required, and he remained stable at review 10 months later.
DISCUSSION Systemic sclerosis may occur as a systemic disease or exist as “localized” form. The 3 recognized clinical variations include the “limited cutaneous” (previously termed CREST syndrome), “diffuse cutaneous,” and “sine scleroderma” forms of disease. The former is characterized by symmetrical skin thickening limited to the distal extremities and face.2 Autoantibodies to certain cellular or extracellular matrix antigens are associated with various forms of scleroderma; these considered to play a role in activating the inflammatory cascades that result in vascular damage and tissue fibrosis.3 Autoantibodies against centromere antigen are associated with a form of limited systemic sclerosis that is associated with severe digital ischemia, pulmonary artery hypertension, sicca syndrome, and calcinosis. Ocular manifestations of systemic sclerosis have also been described; these including keratoconjunctivitis sicca with subsequent shallowing of the conjunctival fornices and eyelid skin changes with telangiectasia.4,5 Orbital involvement, by comparison with eyelid and ocular surface disease, is extremely unusual, with sporadic reports of systemic sclerosis presenting with diplopia or narrowing of the palpebral fissure (presumably due to lacrimal gland enlargement). Superior oblique palsy has also been reported in patients with systemic sclerosis,6,7 with Brown’s syndrome reported in this context.8 Although the patient reported herein had no evidence for extraocular muscle involvement, ophthalmoplegia has been reported previously.9 In addition, Morris et al.10 reported a case of periorbital and extraocular muscle calcification in a patient
e1
Copyright © 2017 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc. Unauthorized reproduction of this article is prohibited.
Ophthal Plast Reconstr Surg, Vol. XX, No. XX, 2017
Case Reports
FIG. 1. Color fundus examination of the left eye showing healthy optic nerve and subretinal fluid in papillomacular bundle (subsequently confirmed with Optical Coherence Tomography imaging).
and telangiectasia—should be carefully examined for the presence of limited cutaneous systemic sclerosis.
REFERENCES
FIG. 2. Axial CT demonstrating 1) relative left proptosis, 2) thickening of the posterior scleral coat with defined nasal and temporal choroidal effusions, and 3) stranding of the orbital adipose tissue.
suffering from limited cutaneous systemic sclerosis. Finally, orbital fat atrophy and enophthalmos have been reported in a single case of linear scleroderma.11 Recently, Esen et al.12 evaluated the choroidal thickness of 120 eyes of 60 patients with systemic scleroderma using enhanced depth optic coherence tomography imaging. Significant choroidal thinning was identified when compared with healthy controls, this supporting the hypothesis of widespread vascular injury in the disease.12 The patient described in this report similarly was noted to have subretinal changes, albeit choroidal effusions early in the course of disease, indicating alterations in choroidal vascular permeability. It would be of interest to follow the choroidal thickness in this patient after the acute phase of disease has fully subsided. Although orbital inflammatory disease is rarely associated with systemic sclerosis, its detection and differentiation from other etiologies are important, because the prognosis of the systemic disease (in addition to orbital inflammation) is improved with the use of oral nonsteroidal preparations. Our report suggests that patients with orbital inflammatory disease—especially in association with Raynaud’s phenomenon
e2
1. Terajima K, Shimohata T, Watanabe M, et al. Cerebral vasculopathy showing moyamoya-like changes in a patient with CREST syndrome. Eur Neurol 2001;46:163–5. 2. Tailor R, Gupta A, Herrick A, et al. Ocular manifestations of scleroderma. Surv Ophthalmol 2009;54:292–304. 3. Boin F, Rosen A. Autoimmunity in systemic sclerosis: current concepts. Curr Rheumatol Rep 2007;9:165–72. 4. Alarcón-Segovia D, Ibánez G, Hernández-Ortíz J, et al. Sjögren’s syndrome in progressive systemic sclerosis (scleroderma). Am J Med 1974;57:78–85. 5. Horan EC. Ophthalmic manifestations of progressive systemic sclerosis. Br J Ophthalmol 1969;53:388–92. 6. Mejias E. Superior oblique muscle paralysis in the CREST syndrome. P R Health Sci J 1986;5:27–9. 7. Shimohata T, Sato T, Akaiwa Y, et al. Isolated trochlear nerve palsy in CREST syndrome. Eur Neurol 2003;50:181–2. 8. Olver J, Laidler P. Acquired Brown’s syndrome in a patient with combined lichen sclerosus et atrophicus and morphoea. Br J Ophthalmol 1988;72:552–7. 9. Arnett FC, Michels RG. Inflammatory ocular myopathy in systemic sclerosis (scleroderma). A case report and review of the literature. Arch Intern Med 1973;132:740–3. 10. Morris OC, Verity DH, Luthert PJ, et al. Orbital bone and soft tissue calcification in CREST syndrome. Clin Exp Ophthalmol 2010;38:534–6. 11. Ramboer K, Demaerel P, Baert AL, et al. Linear scleroderma with orbital involvement: follow up and magnetic resonance imaging. Br J Ophthalmol 1997;81:90–1. 12. Esen E, Tas DA, Sizmaz S, et al. Evaluating choroidal characteristics in systemic sclerosis using enhanced depth imaging optical coherence tomography. Ocul Immunol Inflamm 2017;25:356–62.
© 2017 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.
Copyright © 2017 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc. Unauthorized reproduction of this article is prohibited.
S
ystemic sclerosis is a multisystem disorder of unknown etiology characterized by immune activation, vasculopathy, and marked fibroblast activity. Limited cutaneous systemic sclerosis, previously known as CREST syndrome, is a variant of systemic sclerosis characterized by Calcinosis cutis, Raynaud’s phenomenon, Esophageal dysmotility, Sclerodactyly and Telangiectasia.1 Systemic sclerosis is an uncommon disease, and ocular manifestations have been reported in a very small number of cases. Ocular symptoms can be particularly troublesome and may present long before the systemic diagnosis has been established. The authors describe a patient with limited cutaneous systemic sclerosis who presented with scleritis and dacryoadenitis, which to our knowledge has not previously been reported.
CASE REPORT A 61-year-old male patient of Indian extraction with no significant medical history was referred with a painful swollen left eye over the previous week. On examination, his best-corrected visual acuity was 6/9 in each eye, with no evidence of optic neuropathy. The objective findings included a 2 mm relative left proptosis and a moderate restriction of left ocular ductions in all positions of gaze with symptomatic diplopia being most severe in downgaze. The conjunctiva was injected and chemosed, both lids were swollen, and he was tender on palpation over lacrimal gland; bilateral intraocular pressures were normal. Although fundus examination revealed a healthy appearing optic disc, there was evidence of subretinal fluid in the nasal macula area clinically and on Optical Coherence Tomography imaging *Orbital Service, Moorfields Eye Hospital, and †Rheumatology Department, Guy’s and St Thomas; Hospital, London, United Kingdom Accepted for publication August 5, 2017. The authors have no financial or conflicts of interest to disclose. Address correspondence and reprint requests to David H. Verity, M.D., F.R.C.Ophth, Moorfields Eye Hospital NHS Foundation Trust, City Road, London EC1V 2PD, United Kingdom. E-mail: David.verity@moorfields. nhs.uk DOI: 10.1097/IOP.0000000000001007
Ophthal Plast Reconstr Surg, Vol. XX, No. XX, 2017
(Fig. 1). CT imaging confirmed thickening of the left posterior sclera with an associated choroidal effusion and asymmetric enlargement of the lacrimal gland. Although there was no evidence of extraocular muscle involvement, there was stranding of the subcutaneous soft tissues over the malar, temporalis, and glabellar regions (Fig. 2), and ultrasound examination revealed nasal and temporal elevation due to choroidal effusions. On the presumptive diagnosis of marked scleritis with atypical features, he was treated with Co-amoxiclav (Tini Pharma, Delhi, India) 625 mg tid and a nonsteroidal inflammatory preparation (Flurbiprofen, Taj Pharmaceuticals Limited, Mumbai, India, 50 mg tid) for 1 week. Laboratory investigations revealed strong positivity to antinuclear antibodies of 1:2,560 with a centromere pattern, positive antineutrophil cytoplasmic antibodies, but negative proteinase 3 and myeloperoxidase antibodies. Although the thyroid-stimulating hormone was mildly raised, thyroid antibodies, free thyroxine, angiotensinconverting enzyme, sedimentation rate, and C-reactive protein were all negative or within the respective normal ranges. In view of these findings, he was referred for a rheumatology assessment, and on further questioning, he reported a single typical episode of Raynaud’s disease 20 years previously with a white phase to the discoloration. Three months after his orbital presentation, he then developed digital ulceration of both the hands and the feet, with discoloration of the fingernails and extensive telangiectasia; although there were no other typical features of limited cutaneous systemic sclerosis such as reduced aqueous tear production, breathlessness, dysphagia, or skin changes, he was diagnosed with limited cutaneous systemic sclerosis. In addition, Nailfold video capillaroscopy was performed and revealed very abnormal with grossly dilated capillaries, capillary drop out, and ragged cuticles in keeping with systemic sclerosis. His orbital inflammatory disease promptly responded to the above treatments. No further treatment was required, and he remained stable at review 10 months later.
DISCUSSION Systemic sclerosis may occur as a systemic disease or exist as “localized” form. The 3 recognized clinical variations include the “limited cutaneous” (previously termed CREST syndrome), “diffuse cutaneous,” and “sine scleroderma” forms of disease. The former is characterized by symmetrical skin thickening limited to the distal extremities and face.2 Autoantibodies to certain cellular or extracellular matrix antigens are associated with various forms of scleroderma; these considered to play a role in activating the inflammatory cascades that result in vascular damage and tissue fibrosis.3 Autoantibodies against centromere antigen are associated with a form of limited systemic sclerosis that is associated with severe digital ischemia, pulmonary artery hypertension, sicca syndrome, and calcinosis. Ocular manifestations of systemic sclerosis have also been described; these including keratoconjunctivitis sicca with subsequent shallowing of the conjunctival fornices and eyelid skin changes with telangiectasia.4,5 Orbital involvement, by comparison with eyelid and ocular surface disease, is extremely unusual, with sporadic reports of systemic sclerosis presenting with diplopia or narrowing of the palpebral fissure (presumably due to lacrimal gland enlargement). Superior oblique palsy has also been reported in patients with systemic sclerosis,6,7 with Brown’s syndrome reported in this context.8 Although the patient reported herein had no evidence for extraocular muscle involvement, ophthalmoplegia has been reported previously.9 In addition, Morris et al.10 reported a case of periorbital and extraocular muscle calcification in a patient
e1
Copyright © 2017 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc. Unauthorized reproduction of this article is prohibited.
Ophthal Plast Reconstr Surg, Vol. XX, No. XX, 2017
Case Reports
FIG. 1. Color fundus examination of the left eye showing healthy optic nerve and subretinal fluid in papillomacular bundle (subsequently confirmed with Optical Coherence Tomography imaging).
and telangiectasia—should be carefully examined for the presence of limited cutaneous systemic sclerosis.
REFERENCES
FIG. 2. Axial CT demonstrating 1) relative left proptosis, 2) thickening of the posterior scleral coat with defined nasal and temporal choroidal effusions, and 3) stranding of the orbital adipose tissue.
suffering from limited cutaneous systemic sclerosis. Finally, orbital fat atrophy and enophthalmos have been reported in a single case of linear scleroderma.11 Recently, Esen et al.12 evaluated the choroidal thickness of 120 eyes of 60 patients with systemic scleroderma using enhanced depth optic coherence tomography imaging. Significant choroidal thinning was identified when compared with healthy controls, this supporting the hypothesis of widespread vascular injury in the disease.12 The patient described in this report similarly was noted to have subretinal changes, albeit choroidal effusions early in the course of disease, indicating alterations in choroidal vascular permeability. It would be of interest to follow the choroidal thickness in this patient after the acute phase of disease has fully subsided. Although orbital inflammatory disease is rarely associated with systemic sclerosis, its detection and differentiation from other etiologies are important, because the prognosis of the systemic disease (in addition to orbital inflammation) is improved with the use of oral nonsteroidal preparations. Our report suggests that patients with orbital inflammatory disease—especially in association with Raynaud’s phenomenon
e2
1. Terajima K, Shimohata T, Watanabe M, et al. Cerebral vasculopathy showing moyamoya-like changes in a patient with CREST syndrome. Eur Neurol 2001;46:163–5. 2. Tailor R, Gupta A, Herrick A, et al. Ocular manifestations of scleroderma. Surv Ophthalmol 2009;54:292–304. 3. Boin F, Rosen A. Autoimmunity in systemic sclerosis: current concepts. Curr Rheumatol Rep 2007;9:165–72. 4. Alarcón-Segovia D, Ibánez G, Hernández-Ortíz J, et al. Sjögren’s syndrome in progressive systemic sclerosis (scleroderma). Am J Med 1974;57:78–85. 5. Horan EC. Ophthalmic manifestations of progressive systemic sclerosis. Br J Ophthalmol 1969;53:388–92. 6. Mejias E. Superior oblique muscle paralysis in the CREST syndrome. P R Health Sci J 1986;5:27–9. 7. Shimohata T, Sato T, Akaiwa Y, et al. Isolated trochlear nerve palsy in CREST syndrome. Eur Neurol 2003;50:181–2. 8. Olver J, Laidler P. Acquired Brown’s syndrome in a patient with combined lichen sclerosus et atrophicus and morphoea. Br J Ophthalmol 1988;72:552–7. 9. Arnett FC, Michels RG. Inflammatory ocular myopathy in systemic sclerosis (scleroderma). A case report and review of the literature. Arch Intern Med 1973;132:740–3. 10. Morris OC, Verity DH, Luthert PJ, et al. Orbital bone and soft tissue calcification in CREST syndrome. Clin Exp Ophthalmol 2010;38:534–6. 11. Ramboer K, Demaerel P, Baert AL, et al. Linear scleroderma with orbital involvement: follow up and magnetic resonance imaging. Br J Ophthalmol 1997;81:90–1. 12. Esen E, Tas DA, Sizmaz S, et al. Evaluating choroidal characteristics in systemic sclerosis using enhanced depth imaging optical coherence tomography. Ocul Immunol Inflamm 2017;25:356–62.
© 2017 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc.
Copyright © 2017 The American Society of Ophthalmic Plastic and Reconstructive Surgery, Inc. Unauthorized reproduction of this article is prohibited.
